Global analysis of mutations driving microevolution of a heterozygous diploid fungal pathogen

Iuliana V Ene, Rhys A Farrer, Matthew P Hirakawa, Kennedy Agwamba, Christina A Cuomo, Richard J Bennett

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Candida albicans is a heterozygous diploid yeast that is a commensal of the human gastrointestinal tract and a prevalent opportunistic pathogen. Here, whole-genome sequencing was performed on multiple C. albicans isolates passaged both in vitro and in vivo to characterize the complete spectrum of mutations arising in laboratory culture and in the mammalian host. We establish that, independent of culture niche, microevolution is primarily driven by de novo base substitutions and frequent short-tract loss-of-heterozygosity events. An average base-substitution rate of ∼1.2 × 10-10 per base pair per generation was observed in vitro, with higher rates inferred during host infection. Large-scale chromosomal changes were relatively rare, although chromosome 7 trisomies frequently emerged during passaging in a gastrointestinal model and was associated with increased fitness for this niche. Multiple chromosomal features impacted mutational patterns, with mutation rates elevated in repetitive regions, subtelomeric regions, and in gene families encoding cell surface proteins involved in host adhesion. Strikingly, de novo mutation rates were more than 800-fold higher in regions immediately adjacent to emergent loss-of-heterozygosity tracts, indicative of recombination-induced mutagenesis. Furthermore, genomes showed biased patterns of mutations suggestive of extensive purifying selection during passaging. These results reveal how both cell-intrinsic and cell-extrinsic factors influence C. albicans microevolution, and provide a quantitative picture of genome dynamics in this heterozygous diploid species.

Original languageEnglish
Pages (from-to)E8688-E8697
Issue number37
Early online date27 Aug 2018
Publication statusPublished - 11 Sept 2018

Bibliographical note

Data deposition: The sequence reported in this paper has been deposited in the NCBI Sequence Read Archive, (BioProject ID PRJNA345600).

This article contains supporting information online at


  • Candida albicans/genetics
  • Candidiasis/microbiology
  • Chromosomes, Fungal
  • Diploidy
  • Evolution, Molecular
  • Genome, Fungal/genetics
  • Heterozygote
  • Humans
  • Loss of Heterozygosity
  • Mutation
  • Selection, Genetic


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